Although many highly enantioselective chiral catalysts and catalytic processes are available for the asymmetric hydrogenation and transfer hydrogenation of C═C and C═O bonds, relatively few exist for effective reduction of the analogous C═N function. The production of chiral amines via this methodology still represents a major challenge. Over the past decade, there has been significant and steady progress in this field with the preparation of catalysts based on complexes of rhodium, iridium, ruthenium and titanium.
In 1997 B. R. James reviewed the preparation of chiral amines by homogeneous catalytic hydrogenation reactions involving metal complexes (James, Catalysis Today 1997, 37, 209-221). The review by James names several other systems based on rhodium for the asymmetric hydrogenation of imines but they suffer from drawbacks. Either the enantioselectivity is low or the conditions are severe. In a recent U.S. patent, X. Zhang et al. describe the use of BICP, a chiral diphosphine ligand, on rhodium and iridium in the asymmetric hydrogenation of internal C═N bonds at 1000 psi H2 at room temperature to produce amines with enantiomeric excesses (e.e.) ranging from 65 to 94%. (X. Zhang, U.S. Pat. No. 6,037,500, 2000). Spindler and co-workers demonstrated the use of in situ generated iridium JOSIPHOS complexes for the enantioselective hydrogenation of imines (Spindler et al., Angew. Chem., Int. Ed Engl., 1990, 29, 558; Blaser and Spindler, Topics in Catalysis, 1997, 4, 275). This process was subsequently modified and applied to the industrial production of the imine precursor to (S)-Metolachlor, a valuable agrichemical product, then for Ciba-Giegy, now for Novartis. The production of S-Metolachlor is an example of a large-scale industrial process that depends on the homogenous hydrogenation of a prochiral imine.
Noyori and coworkers have described an efficient catalyst system generated from the complex Ru(η6-arene)(tosyldiamine)Cl for the asymmetric hydrogenation of imines by transferring hydrogen from triethylammonium formate (Noyori et al., Acc. Chem. Res. 1997, 30, 97-102). This is the first really effective imine reduction system based on ruthenium although other straight hydrogenation systems with much lower activity and selectivity have been reported as reviewed by James (supra).
Buchwald and co-workers prepared and effectively employed various chiral ansa-titanocene complexes for both hydrogenation and hydrosilylation of imines (Willoughby and Buchwald, J. Am. Chem. Soc., 1992, 114, 7562; J. Am. Chem. Soc., 1994, 116, 8952 and 11703). The need to activate the catalyst by the addition of butyl-lithium and phenyl silane limits the scope and applicability of this process. This system also suffers from the drawback of being very oxygen and water sensitive.
A recent article by Kobayashi and Ishitani on catalytic enantioselective addition to imines also provides a comprehensive review on other advances in enantioselective hydrogenation of imines (Kobayashi and Ishitani, Chem. Rev., 1999, 99, 1069). These include the use of chiral iridium diphosphine complexes of the type [Ir(P—P)HI2]2 (where P—P represents a chiral diphosphine ligand) reported by Osborn and co-workers (Chan et al., J. Am. Chem. Soc., 1990, 112, 9400; Sablong et al., Tetrahedron Lett., 1996, 37, 4937). These systems were reasonably active, however, the enantioselectivities were only moderate. Zhang and co-workers reported the synthesis of a new class of chiral iridium binaphane complexes (Xiao and Zhang, Angew. Chem. Int. Ed. Engl., 2001, 40, 3425) and their use for the asymmetric hydrogenation of imines. More recently Rautenstrauch et al. (WO 02/22526) reported the use of metal complexes with P—N bidentate ligands in the catalytic hydrogenation of carbon-heteroatom double bonds, including C═N double bonds.
Despite the successes of some of these catalytic hydrogenation processes, there are certain significant drawbacks. These include high operating pressures (typically >50 bar H2), high catalyst loading and the use of expensive iridiun- and rhodium-based systems. Most of these processes are specific for only certain types of substrates or a group of closely related substrates. In addition, activity and enantioselectivity also tends to be highly substrate dependent, which in some cases necessitates the development of an entire catalytic system and process for only one substrate or a very closely related group of substrates.
Hence, there remains the need to identify a general class of structurally related catalysts that are chemically robust and give high activity and enantioselectivity in the asymmetric hydrogenation of a broad range of imine substrates. It is particularly desirable to have a class of modular catalysts whereby one can readily vary individual parts of the catalyst, especially the chiral ligand, so that the best match of substrate and catalyst can be identified by rapid through-put combinatorial screening.
Noyori and co-workers have pioneered the use of ruthenium complexes bearing a chelating diphosphine ligand (or two monodentate phosphines) and a chelating diamine ligand for the catalytic asymmetric hydrogenation of ketones. At least one and usually both of the chelating ligands are chiral. The various papers and patents of Noyori et al. have demonstrated the highly efficient reduction of various functionalised and unfunctionalised ketones using this class of catalysts. It was also demonstrated by Noyori and co-workers (Ohkuma et al., J. Am. Chem. Soc., 1995, 107, 2675 and 10417) that a fully isolated and characterised ruthenium(II)diphosphinediamine complex could be used as catalyst. High activity and high selectivity were generally associated with the use of chiral biaryl-phosphines (eg. Tol-BINAP and Xyl-BINAP) and diamines (eg. DPEN and DAIPEN).
It was demonstrated for the first time by Abdur-Rashid et al. that similar classes of Noyori-type ruthenium(II)(phosphine)2(diamine) complexes (Abdur-Rashid et al., Organometallics, 2000, 20, 1655) or ruthenium(II)diphosphinediamine complexes (Abdur-Rashid et al., Oral and Poster Presentations at the Canadian Society for Chemistry 83rd Conference and Exhibition (Calgary, Alberta), May 2000) could catalyse the hydrogenation and asymmetric hydrogenation of activated (aromatic) imines. Since these publications, Chirotech Technology Limited filed a patent (WO 02/08169 A1) for an imine hydrogenation process, based on a similar class of complexes for the hydrogenation and asymmetric hydrogenation of activated (aromatic) imines. The work presented by Abdur-Rashid et al. at the May 2000 CSC meeting in Calgary was subsequently published in 2001 (Organometallics, 2001, 20, 1047).
The imine hydrogenation work of Abdur-Rashid et al. and the patent of Chirotech Technology Limited relates to the use of Noyori-type ruthenium(II)-(phosphine)2(diamine) and ruthenium(II)diphosphinediamine complexes as catalysts for the reduction of activated imines in which the imine functional group is adjacent to an aromatic aryl ring as illustrated in (I) below.

To date, there are no reports in the mainstream or patent literature of the use of such Noyori-type ruthenium(II) complexes for the hydrogenation and asymmetric hydrogenation of unactivated dialkyl, alkylalkenyl or dialkenyl imines as illustrated in (II), where R1 and R2 represents alkyl, alkylalkenyl or dialkenyl substituents. These imines are inherently more difficult to reduce than their activated (aromatic) analogues, and there are only a few reported attempts in the published and patent literature for the catalytic hydrogenation and asymmetric hydrogenation of such compounds.

The industrial production of the chiral amine precursor to the potent herbicide S-Metolachor using an iridium-JOSIPHOS catalyst is an example of a successful process that relies on the asymmetric hydrogenation of a dialkyl imine (Togni, Angew. Chem, Int. Ed Engl., 1996, 35, 1475).
There remains a need for efficient catalysts for the hydrogenation and asymmetric hydrogenation of unactivated imines.